ALG8

Summary

ALG8 (ALG8 alpha-1,3-glucosyltransferase, HGNC:23161) is a protein-coding gene on chromosome 11q14.1, encoding Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (Q9BVK2). Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation. It is a selective cancer dependency (DepMap: 21.4% of cell lines).

This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 79053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant polycystic kidney disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 484 total — 18 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 93
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 21.4% of screened cell lines
• MANE Select transcript: NM_024079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23161
Approved symbol	ALG8
Name	ALG8 alpha-1,3-glucosyltransferase
Location	11q14.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC2840
Ensembl gene	ENSG00000159063
Ensembl biotype	protein_coding
OMIM	608103
Entrez	79053

Gene structure

Transcript identifiers

Ensembl transcripts: 80 — 52 protein_coding, 20 nonsense_mediated_decay, 5 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000299626, ENST00000376156, ENST00000524925, ENST00000525755, ENST00000525761, ENST00000525783, ENST00000525870, ENST00000526737, ENST00000526849, ENST00000526928, ENST00000527099, ENST00000529139, ENST00000530454, ENST00000530608, ENST00000530910, ENST00000531213, ENST00000532050, ENST00000532306, ENST00000532440, ENST00000532552, ENST00000615266, ENST00000679444, ENST00000679497, ENST00000679539, ENST00000679559, ENST00000679581, ENST00000679648, ENST00000679685, ENST00000679697, ENST00000679874, ENST00000679986, ENST00000680063, ENST00000680101, ENST00000680142, ENST00000680223, ENST00000680256, ENST00000680329, ENST00000680398, ENST00000680399, ENST00000680459, ENST00000680467, ENST00000680499, ENST00000680580, ENST00000680643, ENST00000680650, ENST00000680761, ENST00000680797, ENST00000680829, ENST00000680866, ENST00000680996, ENST00000681221, ENST00000681225, ENST00000681351, ENST00000681384, ENST00000681417, ENST00000681489, ENST00000681575, ENST00000681699, ENST00000681723, ENST00000681765, ENST00000681853, ENST00000681957, ENST00000853767, ENST00000853768, ENST00000853769, ENST00000853770, ENST00000853771, ENST00000853772, ENST00000853773, ENST00000853774, ENST00000853775, ENST00000853776, ENST00000853777, ENST00000925534, ENST00000925536, ENST00000925537, ENST00000925538, ENST00000925539, ENST00000925540, ENST00000965607

RefSeq mRNA: 27 — MANE Select: NM_024079 NM_001007027, NM_001425219, NM_001425220, NM_001425221, NM_001425222, NM_001425223, NM_001425224, NM_001425225, NM_001425226, NM_001425227, NM_001425228, NM_001425229, NM_001425230, NM_001425231, NM_001425232, NM_001425233, NM_001425234, NM_001425235, NM_001425236, NM_001425237, NM_001425238, NM_001425239, NM_001425240, NM_001425241, NM_001425242, NM_001425243, NM_024079

CCDS: CCDS41692, CCDS8258

Canonical transcript exons

ENST00000299626 — 13 exons

Exon	Start	End
ENSE00001103524	78121065	78121174
ENSE00002176930	78139494	78139626
ENSE00003471595	78119182	78119249
ENSE00003551223	78103980	78104052
ENSE00003575058	78113886	78113989
ENSE00003597834	78100946	78101195
ENSE00003612997	78127358	78127436
ENSE00003629152	78104356	78104453
ENSE00003645223	78109442	78109581
ENSE00003681314	78112650	78112770
ENSE00003784842	78114266	78114392
ENSE00003786090	78124021	78124214
ENSE00003788130	78106807	78106946

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 94.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.0240 / max 367.6164, expressed in 1804 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121467	32.0240	1804

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	94.84	gold quality
left testis	UBERON:0004533	94.69	gold quality
testis	UBERON:0000473	94.02	gold quality
colonic epithelium	UBERON:0000397	93.81	gold quality
adrenal tissue	UBERON:0018303	93.56	gold quality
ventricular zone	UBERON:0003053	93.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.14	gold quality
right lobe of liver	UBERON:0001114	93.06	gold quality
right adrenal gland	UBERON:0001233	92.76	gold quality
left adrenal gland cortex	UBERON:0035825	92.71	gold quality
left adrenal gland	UBERON:0001234	92.68	gold quality
stromal cell of endometrium	CL:0002255	92.55	gold quality
right adrenal gland cortex	UBERON:0035827	92.55	gold quality
ganglionic eminence	UBERON:0004023	92.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.44	gold quality
adrenal gland	UBERON:0002369	92.43	gold quality
adrenal cortex	UBERON:0001235	92.31	gold quality
mucosa of transverse colon	UBERON:0004991	92.24	gold quality
right lobe of thyroid gland	UBERON:0001119	92.03	gold quality
rectum	UBERON:0001052	91.42	gold quality
left lobe of thyroid gland	UBERON:0001120	91.41	gold quality
right uterine tube	UBERON:0001302	91.39	gold quality
thyroid gland	UBERON:0002046	91.22	gold quality
tibial nerve	UBERON:0001323	90.98	gold quality
right ovary	UBERON:0002118	90.98	gold quality
body of pancreas	UBERON:0001150	90.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.86	gold quality
nucleus accumbens	UBERON:0001882	90.85	gold quality
liver	UBERON:0002107	90.81	gold quality
adenohypophysis	UBERON:0002196	90.77	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.78
E-CURD-112	no	3.78

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 21.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• ALG8 splice site mutations and missense mutations causing ALG8 deficiency in patients with congenital disorders of glycosylation type Ih. (PMID:15235028)
• ALG8 mutations expand the clinical spectrum of congenital disorder of glycosylation type Ih. (PMID:19648040)
• Severe ALG8 congenital disorder of glycosylation(CDG-Ih) is associated with homozygosity for two novel missense mutations in exon 8 of ALG8 (PMID:22306853)
• We reviewed the clinical features in all nine previously reported patients diagnosed with ALG8-disorder of glycosylation with a special focus on their skin signs. (PMID:24555185)
• In ALG8-CDG, isoelectric focusing of transferrin in serum or plasma shows an abnormal sialotransferrin pattern. The diagnosis is confirmed by mutation analysis in ALG8; all patients reported so far had point mutations or small deletions (PMID:26066342)
• used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common polycystic liver disease genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. (PMID:28375157)
• analysis of genetic variants in ALG8 in patients with congenital disorders of glycosylation (PMID:30420707)
• ALG8 Fuels Stemness Through Glycosylation of the WNT/Beta-Catenin Signaling Pathway in Colon Cancer. (PMID:36454274)
• Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease. (PMID:36574950)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alg8	ENSDARG00000044627
mus_musculus	Alg8	ENSMUSG00000035704
rattus_norvegicus	Alg8	ENSRNOG00000012292
drosophila_melanogaster	xit	FBGN0029906
caenorhabditis_elegans		WBGENE00007464

Paralogs (1): ALG6 (ENSG00000088035)

Protein

Protein identifiers

Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase — Q9BVK2 (reviewed: Q9BVK2)

Alternative names: Asparagine-linked glycosylation protein 8 homolog, Dol-P-Glc:Glc(1)Man(9)GlcNAc(2)-PP-dolichyl alpha-1,3-glucosyltransferase, Dolichyl-P-Glc:Glc1Man9GlcNAc2-PP-dolichyl glucosyltransferase

All UniProt accessions (32): Q9BVK2, A0A024R5K5, A0A7P0T810, A0A7P0T837, A0A7P0T845, A0A7P0T8Q8, A0A7P0T919, A0A7P0T9A3, A0A7P0T9F4, A0A7P0T9H4, A0A7P0T9J9, A0A7P0T9Q0, A0A7P0T9Y0, A0A7P0TA89, A0A7P0TAA1, A0A7P0TAA8, A0A7P0TAL7, A0A7P0TB84, A0A7P0Z449, A0A7P0Z4J4, A0A804G6E3, E9PK79, E9PKA5, E9PNE2, E9PP80, E9PP96, E9PR58, H0YCV0, H0YD42, H0YDD3, H0YDV4, H0YEE0

UniProt curated annotations — full annotation on UniProt →

Function. Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation. The assembly of dolichol-linked oligosaccharides begins on the cytosolic side of the endoplasmic reticulum membrane and finishes in its lumen. The sequential addition of sugars to dolichol pyrophosphate produces dolichol-linked oligosaccharides containing fourteen sugars, including two GlcNAcs, nine mannoses and three glucoses. Once assembled, the oligosaccharide is transferred from the lipid to nascent proteins by oligosaccharyltransferases. In the lumen of the endoplasmic reticulum, adds the second glucose residue from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide intermediate Glc(1)Man(9)GlcNAc(2)-PP-Dol to produce Glc(2)Man(9)GlcNAc(2)-PP-Dol. Glc(2)Man(9)GlcNAc(2)-PP-Dol is a substrate for ALG10, the following enzyme in the biosynthetic pathway. Required for PKD1/Polycystin-1 maturation and localization to the plasma membrane of the primary cilia.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1H (CDG1H) [MIM:608104] A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry. Polycystic liver disease 3 with or without kidney cysts (PCLD3) [MIM:617874] A form of polycystic liver disease, an autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. PCLD3 patients may also develop kidney cysts that usually do not result in clinically significant renal disease. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the ALG6/ALG8 glucosyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BVK2-1	1	yes
Q9BVK2-2	2

RefSeq proteins (27): NP_001007028, NP_001412148, NP_001412149, NP_001412150, NP_001412151, NP_001412152, NP_001412153, NP_001412154, NP_001412155, NP_001412156, NP_001412157, NP_001412158, NP_001412159, NP_001412160, NP_001412161, NP_001412162, NP_001412163, NP_001412164, NP_001412165, NP_001412166, NP_001412167, NP_001412168, NP_001412169, NP_001412170, NP_001412171, NP_001412172, NP_076984* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004856	Glyco_trans_ALG6/ALG8	Family

Pfam: PF03155

Enzyme classification (BRENDA):

• EC 2.4.1.265 — dolichyl-P-Glc:Glc1Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase (BRENDA: 4 organisms, 1 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• an alpha-D-Glc-(1->3)-alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + a di-trans,poly-cis-dolichyl beta-D-glucosyl phosphate = an alpha-D-Glc-(1->3)-alpha-D-Glc-(1->3)-alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:31307)

UniProt features (21 total): transmembrane region 11, sequence variant 6, sequence conflict 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BVK2-F1	92.07	0.82

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-4724325	Defective ALG8 causes CDG-1h
R-HSA-1643685	Disease
R-HSA-3781860	Diseases associated with N-glycosylation of proteins
R-HSA-3781865	Diseases of glycosylation
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 355 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, KEGG_N_GLYCAN_BIOSYNTHESIS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, MORF_ATOX1, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MAGRANGEAS_MULTIPLE_MYELOMA_IGLL_VS_IGLK_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, GOCC_LUMENAL_SIDE_OF_MEMBRANE, MORF_MSH2, MARSON_BOUND_BY_FOXP3_STIMULATED

GO Biological Process (4): protein N-linked glycosylation (GO:0006487), dolichol-linked oligosaccharide biosynthetic process (GO:0006488), obsolete protein N-linked glycosylation via asparagine (GO:0018279), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (6): dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity (GO:0004583), dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity (GO:0042283), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hexosyltransferase activity (GO:0016758)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), lumenal side of endoplasmic reticulum membrane (GO:0098553), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Asparagine N-linked glycosylation	1
Diseases associated with N-glycosylation of proteins	1
Diseases of glycosylation	1
Diseases of metabolism	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycoprotein biosynthetic process	1
protein N-linked glycosylation	1
carbohydrate derivative biosynthetic process	1
glucosyltransferase activity	1
dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
glycosyltransferase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum membrane	1
lumenal side of membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALG8	ALG12	Q9BV10	872
ALG8	PMM2	O15305	858
ALG8	ALG3	Q92685	839
ALG8	ALG5	Q9Y673	811
ALG8	GANAB	Q14697	805
ALG8	ALG1	Q9BT22	794
ALG8	DPAGT1	Q9H3H5	759
ALG8	ALG11	Q2TAA5	758
ALG8	PRKCSH	P14314	719
ALG8	ALG6	Q9Y672	718
ALG8	ALG13	Q9NP73	718
ALG8	DPM1	O60762	714
ALG8	ALG14	Q96F25	710
ALG8	SEC61B	P38390	698
ALG8	SEC63	Q9UGP8	687

IntAct

94 interactions, top by confidence:

A	B	Type	Score
ALG8	CREB3	psi-mi:“MI:0915”(physical association)	0.560
BIK	ALG8	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	ALG8	psi-mi:“MI:0915”(physical association)	0.560
CYB5R3	ALG8	psi-mi:“MI:0915”(physical association)	0.560
ALG8	SAR1A	psi-mi:“MI:0915”(physical association)	0.560
MFSD6	ALG8	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	ALG8	psi-mi:“MI:0915”(physical association)	0.560
CLRN1	ALG8	psi-mi:“MI:0915”(physical association)	0.560
GPX8	ALG8	psi-mi:“MI:0915”(physical association)	0.560
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
CCDC107	PLD2	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
GPR52	SYNGR2	psi-mi:“MI:0914”(association)	0.530
RPN2	SMPD2	psi-mi:“MI:0914”(association)	0.530
TM2D2	TMEM97	psi-mi:“MI:0914”(association)	0.530
	UBXN8	psi-mi:“MI:0914”(association)	0.530
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
ALG6	ALG8	psi-mi:“MI:0915”(physical association)	0.500
NAE1	ALG8	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA5	ALG8	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (76): ALG8 (Affinity Capture-RNA), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), CREB3 (Two-hybrid), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS), ALG8 (Affinity Capture-MS)

ESM2 similar proteins: A1CBE6, A1DDZ3, A2RA94, A3LTB7, A5DJQ5, O43053, O80505, O82244, P0CN92, P0CN93, P38179, P47088, P82149, Q0P5D9, Q10479, Q12001, Q1DJR8, Q27333, Q2HA14, Q2TXB8, Q2U6A4, Q2UB20, Q4I073, Q4I0K3, Q4IJT0, Q4R4E1, Q4WAH2, Q4WVG2, Q5B7W0, Q5EA10, Q5RAH7, Q66IJ4, Q6BYY8, Q6C216, Q6CAB8, Q6CMF1, Q6DNA2, Q6FXQ5, Q6FXS2, Q6P8H8

Diamond homologs: O43053, Q09226, Q10479, Q12001, Q2UB20, Q3T1L5, Q3TAE8, Q54QG6, Q5NVS8, Q6P8H8, Q7RXP5, Q802T2, Q9BVK2, Q9FF17, Q9VKX7, Q9Y672, O80505, P40351, P52887, Q0P5D9, Q1DJR8, Q2HA14, Q4IJT0, Q554E2, Q5AJD2, Q5AWM9, Q6BRE5, Q6CJR2, Q6FKM3, Q759R3, Q9W3V8, A7FNH1, B0RQR6, B1LAF7, B2IWL4, B9K7P3, O66824, Q0A5M1, Q1DC68, Q2NWR1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	6	15.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

484 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	36
Uncertain significance	215
Likely benign	102
Benign	65

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064698	NM_024079.5(ALG8):c.479A>T (p.His160Leu)	Pathogenic
1342864	NM_024079.5(ALG8):c.1219_1220del (p.Leu407fs)	Pathogenic
1406714	NM_024079.5(ALG8):c.802C>T (p.Arg268Ter)	Pathogenic
2015614	NM_024079.5(ALG8):c.141_144del (p.His48fs)	Pathogenic
2123918	NM_024079.5(ALG8):c.259C>T (p.Gln87Ter)	Pathogenic
2506352	NM_024079.5(ALG8):c.160C>T (p.Gln54Ter)	Pathogenic
2506354	NM_024079.5(ALG8):c.371del (p.Cys124fs)	Pathogenic
2506356	NM_024079.5(ALG8):c.1501del (p.Ala500_Val501insTer)	Pathogenic
2558	NM_024079.5(ALG8):c.413del (p.Thr138fs)	Pathogenic
2560	NM_024079.5(ALG8):c.96-2A>G	Pathogenic
2561	NM_024079.5(ALG8):c.139A>C (p.Thr47Pro)	Pathogenic
2977771	NM_024079.5(ALG8):c.1353dup (p.Glu452fs)	Pathogenic
3244664	NC_000011.9:g.(?77850520)(77850634_?)del	Pathogenic
3350087	NM_024079.5(ALG8):c.1212_1214delinsAA (p.Phe406_Leu407insTer)	Pathogenic
3693026	NM_024079.5(ALG8):c.1098_1101del (p.Thr367fs)	Pathogenic
4038361	NM_024079.5(ALG8):c.689G>A (p.Trp230Ter)	Pathogenic
4531361	NM_024079.5(ALG8):c.967C>T (p.Gln323Ter)	Pathogenic
96091	NM_024079.5(ALG8):c.122G>A (p.Arg41Gln)	Pathogenic
1328207	NM_024079.5(ALG8):c.685C>T (p.Arg229Ter)	Likely pathogenic
1333512	NM_024079.5(ALG8):c.710_719dup (p.Leu241fs)	Likely pathogenic
1344961	NM_024079.5(ALG8):c.95+1G>A	Likely pathogenic
2118558	NM_024079.5(ALG8):c.174+2del	Likely pathogenic
2441122	NM_024079.5(ALG8):c.674-2A>T	Likely pathogenic
2562	NM_024079.5(ALG8):c.673+4A>G	Likely pathogenic
2563	NM_024079.5(ALG8):c.824G>A (p.Gly275Asp)	Likely pathogenic
2628603	NM_024079.5(ALG8):c.777+1G>A	Likely pathogenic
2683953	NM_024079.5(ALG8):c.544C>T (p.Gln182Ter)	Likely pathogenic
2796277	NM_024079.5(ALG8):c.368+1G>A	Likely pathogenic
3347517	NM_024079.5(ALG8):c.705del (p.Phe235fs)	Likely pathogenic
3347910	NM_024079.5(ALG8):c.898+1G>T	Likely pathogenic

SpliceAI

2046 predictions. Top by Δscore:

Variant	Effect	Δscore
11:78103975:ATTAC:A	donor_loss	1.0000
11:78103976:TTA:T	donor_loss	1.0000
11:78103977:TACCT:T	donor_loss	1.0000
11:78103978:A:C	donor_loss	1.0000
11:78103979:CCTGA:C	donor_loss	1.0000
11:78124019:A:AC	donor_gain	1.0000
11:78124020:C:CC	donor_gain	1.0000
11:78124020:CTCA:C	donor_gain	1.0000
11:78124023:A:AC	donor_gain	1.0000
11:78124024:C:CC	donor_gain	1.0000
11:78124024:CGGA:C	donor_gain	1.0000
11:78124048:T:TA	donor_gain	1.0000
11:78101191:CTTTT:C	acceptor_gain	0.9900
11:78101192:TTTT:T	acceptor_gain	0.9900
11:78101193:TTT:T	acceptor_gain	0.9900
11:78101194:TT:T	acceptor_gain	0.9900
11:78101194:TTCT:T	acceptor_loss	0.9900
11:78101195:TCTGA:T	acceptor_loss	0.9900
11:78101196:C:CC	acceptor_gain	0.9900
11:78101196:CTG:C	acceptor_loss	0.9900
11:78101197:T:A	acceptor_loss	0.9900
11:78103974:GATTA:G	donor_loss	0.9900
11:78104053:C:CC	acceptor_gain	0.9900
11:78104454:C:CC	acceptor_gain	0.9900
11:78124020:CT:C	donor_gain	0.9900
11:78127434:TGG:T	acceptor_gain	0.9900
11:78127435:GG:G	acceptor_gain	0.9900
11:78127437:C:CC	acceptor_gain	0.9900
11:78139492:A:AC	donor_gain	0.9900
11:78139493:C:CC	donor_gain	0.9900

AlphaMissense

3405 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:78106840:T:A	E382V	0.999
11:78106837:T:A	K383I	0.998
11:78127410:C:G	R41P	0.998
11:78112692:A:G	W286R	0.997
11:78112692:A:T	W286R	0.997
11:78112707:A:G	W281R	0.997
11:78112707:A:T	W281R	0.997
11:78114342:C:A	K199N	0.997
11:78114342:C:G	K199N	0.997
11:78127405:A:G	W43R	0.997
11:78127405:A:T	W43R	0.997
11:78106840:T:G	E382A	0.996
11:78106839:T:A	E382D	0.995
11:78106839:T:G	E382D	0.995
11:78112696:G:C	N284K	0.995
11:78112696:G:T	N284K	0.995
11:78114343:T:A	K199M	0.995
11:78119239:A:C	F163L	0.995
11:78119239:A:T	F163L	0.995
11:78119241:A:G	F163L	0.995
11:78127369:A:G	W55R	0.995
11:78127369:A:T	W55R	0.995
11:78104394:C:T	G413E	0.994
11:78104395:C:G	G413R	0.994
11:78104395:C:T	G413R	0.994
11:78106846:A:T	V380D	0.994
11:78106838:T:G	K383Q	0.993
11:78106863:A:C	F374L	0.993
11:78106863:A:T	F374L	0.993
11:78106865:A:G	F374L	0.993

dbSNP variants (sampled 300 via entrez): RS1000077786 (11:78126157 T>C), RS1000186011 (11:78120261 C>T), RS1000389042 (11:78136449 G>A,C), RS1000461666 (11:78132194 C>A), RS1000469197 (11:78121701 T>G), RS1000540941 (11:78122079 T>C), RS1000546647 (11:78127006 G>A), RS1000629450 (11:78115537 C>G), RS1000664036 (11:78120622 C>T), RS1000704604 (11:78121382 C>T), RS1000835077 (11:78110334 G>A), RS1000888724 (11:78110024 C>A,T), RS1000989697 (11:78137681 T>G), RS1001017151 (11:78104712 C>G,T), RS1001047220 (11:78132575 T>C)

Disease associations

OMIM: gene MIM:608103 | disease phenotypes: MIM:608104, MIM:617874, MIM:174050

GenCC curated gene-disease

Disease	Classification	Inheritance
ALG8-congenital disorder of glycosylation	Definitive	Autosomal recessive
polycystic liver disease 3 with or without kidney cysts	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal dominant polycystic kidney disease	Definitive	AD

Mondo (4): ALG8-congenital disorder of glycosylation (MONDO:0011969), polycystic liver disease 3 with or without kidney cysts (MONDO:0054743), autosomal dominant polycystic liver disease (MONDO:0000447), familial cystic renal disease (MONDO:0019741)

Orphanet (3): ALG8-CDG (Orphanet:79325), Isolated polycystic liver disease (Orphanet:2924), Genetic cystic renal disease (Orphanet:93587)

HPO phenotypes

93 total (30 of 93 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000107	Renal cyst
HP:0000158	Macroglossia
HP:0000239	Large fontanelles
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000470	Short neck
HP:0000478	Abnormality of the eye
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000707	Abnormality of the nervous system
HP:0000821	Hypothyroidism
HP:0000952	Jaundice
HP:0000969	Edema
HP:0000973	Cutis laxa
HP:0001001	Abnormality of subcutaneous fat tissue
HP:0001156	Brachydactyly
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001396	Cholestasis
HP:0001407	Hepatic cysts
HP:0001410	Decreased liver function
HP:0001508	Failure to thrive

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006427_44	Depression in smokers	9.000000e-06
GCST007277_15	Tourette syndrome	5.000000e-06
GCST012490_320	Femur bone mineral density x serum urate levels interaction	2.000000e-09
GCST012490_622	Femur bone mineral density x serum urate levels interaction	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535746	Congenital disorder of glycosylation type 1H (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067106 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.42	Kd	37.74	nM	CHEMBL3752910
7.42	ED50	37.74	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147847: Binding affinity to human ALG8 incubated for 45 mins by Kinobead based pull down assay	kd	0.0377	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Acetaminophen	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cyclosporine	decreases expression	2
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	decreases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
pyrimidifen	increases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	1
Bile Acids and Salts	increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1
Rotenone	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650889	Binding	Binding affinity to human ALG8 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D6IB	AOUMEYi001-A	Induced pluripotent stem cell	Male
CVCL_SC30	HAP1 ALG8 (-) 1	Cancer cell line	Male
CVCL_SC31	HAP1 ALG8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

17 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01157858	PHASE2	COMPLETED	Everolimus and LongActing Octreotide Trial in Polycystic Livers
NCT01670110	PHASE2	COMPLETED	Pasireotide LAR in Severe Polycystic Liver Disease
NCT02021110	PHASE2	COMPLETED	Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease
NCT05478083	PHASE2	RECRUITING	A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease
NCT00426153	PHASE2/PHASE3	COMPLETED	Octreotide in Severe Polycystic Liver Disease
NCT00565097	PHASE2/PHASE3	COMPLETED	Lanreotide as Treatment of Polycystic Livers
NCT00771888	PHASE2/PHASE3	UNKNOWN	Open-Label Extension of LOCKCYST Trial
NCT01315795	PHASE2/PHASE3	COMPLETED	Lanreotide Autogel in the Treatment of Symptomatic Polycystic Liver Disease
NCT05281328	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Assess the Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With PLD
NCT00934791	Not specified	TERMINATED	Polycystic Liver Disease in Kidney Transplant
NCT01354405	Not specified	COMPLETED	Somatostatin Analogues as a Volume Reducing Treatment of Polycystic Livers (RESOLVE)
NCT02173080	Not specified	COMPLETED	Development and Assessment of The Polycystic Liver Disease Questionnaire (PLD-Q).
NCT03960710	Not specified	UNKNOWN	Automatic Segmentation of Polycystic Liver
NCT04111692	Not specified	RECRUITING	A Prospective Observational Study of Foam Sclerotherapy .
NCT04645251	Not specified	RECRUITING	Polycystic Liver Disease Registry (UK)
NCT05215964	Not specified	UNKNOWN	The Association Between Skeletal Muscle Mass and Severity of Polycystic Liver Disease and Polycystic Kidney Disease
NCT05500157	Not specified	UNKNOWN	Assessment of Treatment With Laparoscopic Fenestration or Aspiration Sclerotherapy for Large Symptomatic Hepatic Cysts